The mechanisms of determinant-specific Ir gene control and of antigen recognition by T and B lymphocytes were explored at several levels in the response to myoglobin. In vitro secondary antibody responses were controlled by the same two determinant-specific Ir genes as the in vivo response, were macrophage and T cell dependent, and seemed to reflect restrictions on T cell-B cell interactions. The antibody response to equine myoglobin, under completely different control from that for sperm whale, required a gene in H-2D, unusual for an antibody response. For staphylococcal nuclease, Ir genes in two high responder haplotypes were found to be nonallelic. Monoclonal antibodies, models of B cell receptors, were found to recognize topographic antigenic determinants, not previously recognized for myoglobin, consisting of residues far apart in the primary sequence but brought together by the folding of the native molecule. Two of these monoclonal antibodies, with different specificities, nevertheless share an idiotope(s) in the combining site. The determinants recognized by some T cell populations have been similarly identified. Both T cells and antibodies are surprisingly sensitive to Glu -- greater than Asp substitutions.